Primary CNS malignancies in adults are uniformly fatal, accounting or approximately 12,000 deaths annually in the United States. There has been little change in the outcome, despite improvements in diagnostic and surgical techniques and advances in radiation therapy. Chemotherapy provides little palliation. This study will evaluate the use of adenovirus-mediated transfer of the drug susceptibility gene herpes virus thymidine kinase (HSV-TK) into primary brain tumors followed by systemic treatment with ganciclovir. The aims are (l) to determine the clinical and histological toxicity of intra-tumor injection of recombinant adenovirus expressing HSV-TK (H5.O1ORSV-TK), followed by intravenous ganciclovir, in patients with recurrent glioma, and (2) to assess the response of malignant glioma to this treatment by brain imaging with volumetric MRI scans and positron emission tomography with l8F- fluorodeoxyglucose. The patients must have gliomas recurrent after radiation therapy, tumors accessible for stereotactic injection and good performance status. Half the patients (those with unresectable lesions) will receive stereotactic-guided injections of the virus into the brain tumor, followed by intravenous ganciclovir for 14 days. The other patients (those with tumors amenable to surgical debulking) will receive the same treatment, except at day 7 their tumors will be surgically resected, and a second dose of virus will be injected into the residual, unresectable portion of the tumor. Intravenous ganciclovir will be continued for an additional 14 days. Patients will be enrolled in groups of three, with each group receiving successively larger doses of adenovirus. Tissue removed at the time of resection will be analyzed for evidence of adenovirus protein expression, RSV-TK DNA (by PCR), inflammation, encephalitis, and tumor necrosis. The patient's humoral immunologic response will be analyzed using western blot and neutralizing antibody assays of serum for anti-adenovirus antibodies. Their cellular immune response will be assessed with peripheral blood lymphocyte proliferation and cytotoxic T-cell assays. Patients will be monitored for development of increased intracranial pressure, surgical complications, and dissemination of the virus to CSF, blood, feces, respirating secretions, and urine. The size and metabolic activity of the tumors after treatment will be assessed by volumetric MRI scans and PET scans. This study will determine the safety of intracranially administered recombinant adenoviruses. It will also provide evidence for efficacy of adenovirally administered HSV-TK and provide valuable information for the development of future vectors.